Abnormal mineralization occurs in the context of several common conditions, including advanced age, diabetes, hypercholesterolemia, chronic renal failure and certain genetic conditions. Loss-of-function mutations in the ABCC6 gene cause chronic or acute forms of dystrophic mineralization in diseases such as Pseudoxanthoma elasticum (PXE) and dystrophic cardiac calcification (DCC). These pathologies are characterized by mineralization of cardiovascular and/or dermal tissues. PXE is heritable while DCC is an acquired phenotype resulting from cardiovascular insults. We have obtained preliminary data that suggest that ABCC6 initiates and modulates a calcification inhibitor pathway with a crucial role in both acute and chronic dystrophic calcification. We hypothesize that the loss of ABCC6 function in liver produces an imbalance of modulators of calcification in cardiovascular tissues either directly or through increased levels or modification of a circulating factor. To test this hypothesis, we will use a mouse models to characterize the effects of ABCC6 mutations on the structure and function of the protein, determine the response of Abcc6-/- mice to acute ischemic cardiac injuries and determine the role of Abcc6-/- in the calcification of the atherosclerotic plaque.

Public Health Relevance

The overall goal of this proposal is to address the role of the ABCC6 gene in chronic and acute dystrophic calcification that affects cardiac and vascular tissues. To achieve the goals of this proposal, we will use mouse models to characterize the effects of ABCC6 mutations on the structure and function of the protein, determine the response of Abcc6-/- mice to acute cardiac ischemic injuries and determine the role of Abcc6 in the calcification of the atherosclerotic plaque.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL108249-02
Application #
8433315
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Reid, Diane M
Project Start
2012-02-24
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$345,100
Indirect Cost
$107,100
Name
University of Hawaii
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
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